| Autor: |
Guillem Pascual-Pasto, Brendan McIntyre, Margaret G. Hines, Anna M. Giudice, Laura Garcia-Gerique, Jennifer Hoffmann, Pamela Mishra, Stephanie Matlaga, Simona Lombardi, Rawan Shraim, Patrick M. Schürch, Mark Yarmarkovich, Ted J. Hofmann, Fatemeh Alikarami, Daniel Martinez, Matthew Tsang, Luis Gil-de-Gómez, Timothy T. Spear, Kathrin M. Bernt, Adam J. Wolpaw, Dimiter S. Dimitrov, Wei Li, Kristopher R. Bosse |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-19 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-51337-2 |
| Popis: |
Abstract Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity. In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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Full text from SpringerLink